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Food Science and Human Wellness 2 (2013) 167–172

Microbiota associated with type 2 diabetes and its related complications

Yong Zhang, Heping Zhang ∗Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Department of Food Science and Engineering,

Inner Mongolia Agricultural University, Hohhot 010018, PR China

Received 10 June 2013; received in revised form 30 August 2013; accepted 23 September 2013

bstract

Recently, it has been established that the human resident microbiota plays key roles in health maintenance. Therefore, it has become anmerging prevention and treatment target for metabolic syndrome. The resident microbiota associated with chronic inflammation has been showno contribute to the onset of type 2 diabetes mellitus (T2DM). Moreover, the microbiota is altered in the development of T2DM and its comorbid

edical conditions/diseases, including diabetic retinopathy, kidney toxicity, atherosclerosis, hypertension, diabetic foot ulcers, cycstic fibrosis andlzheimer’s disease. Besides, some anti-T2DM regimens are also based microbiota metabolism-dependent mechanism. This review summarizes

he current knowledge concerning the altered microbiota in the pathogenesis of T2DM and its related complications, which provides novel insightsnto these diseases and the potential intervention strategies from the microbiology point of view.

2013 Beijing Academy of Food Sciences. Production and hosting by Elsevier B.V. All rights reserved.

eywords: Microbiota; Type 2 diabetes; T2DM complications

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. Introduction

The rapid increase of cases of type 2 diabetes mellitusT2DM) in the past decades has made it a widespread metabolicisorder. In recent years, an increasing understanding of howur microflora is linked to obesity-related T2DM has provided aew potential target for reducing the risk of T2DM. The humanody reservoir harbors trillions of bacteria and the genetic con-ent of the gut microbiome is 150 times more than that of otherarts of the human body [1]. However, the host–microbe inter-ctions have not been fully elucidated. The aim of this review iso expand our view on key roles of microflora during the onsetnd development of T2DM as well as its complications.

∗ Corresponding author at: The Key Laboratory of Dairy Biotechnology andngineering, Ministry of Education, 306 Zhaowudalu Road, Hohhot 010018,R China. Tel.: +86 471 4309940; fax: +86 471 4300122.

E-mail address: hepingdd@vip.sina.com (H. Zhang).eer review under responsibility of Beijing Academy of Food Sciences.

213-4530 © 2013 Beijing Academy of Food Sciences. Production andosting by Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.fshw.2013.09.002

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.1. Gut microbiota in the pathogensis of type 2 diabetes

It is well established that the gut microbiota is involved inhe process of energy harvest accounting for the developmentf obesity [2]. Some researches support the view that the guticrobiota is essential for the host immunity development [3].s one of the most concerned obesity-related disorders, T2DM

s associated with abnormal energy metabolism and low-levelhronic inflammation in fat tissues [4,5]. Some hypotheses haveroposed its relation with the presence of gut microbiota.

Principally, the gut microbiota plays an important role inhe progression of prediabetes conditions, such as insulin resis-ance. Growing evidence in clinical studies suggested thatbese people with insulin resistance were characterized byn altered composition of gut microbiota, particularly an ele-ated Firmicutes/Bacteroidetes ratio compared with healthyeople [6,7]. Furthermore, transplantation of the obese guticrobiota in animals greatly affected the energy harvest of

osts [7]. Consequently, it is proposed that altered micro-iota in obesity modulates intestinal permeability and increasesetabolic endotoxin secretion that lead to chronic low-level

nflammation, the pathogensis of insulin resistance and onsetf T2DM. [8,9]. Recently, commensal bacterial species, such asacteroidetes thetaiotaomicron, Akkermansia muciniphila andscherichia coli, were showed to have different influence on the

ntestinal mucus and glycocalyx layer, which may affect intesti-al permeability [10]. Besides, microbiota-dependent changesn gut tight-junction proteins, endocannabinoid system and

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ntestinal alkaline phosphatase activity may be also involvedn altered intestinal permeability and the pathogensis of insulinesistance [9].

Moreover, the vicious circle between altered microbiota andhe triggered low-level inflammation has also been considereds a deterioration factor in the development of T2DM. Accu-ulating evidence has revealed that T2DM patients exhibited

n altered intestinal microbiota which was characterized by decrease of Bacteroidetes/Firmicutes ratio and some func-ional bacteria (e.g. Bifidobacteria) with an increase of variouspportunistic pathogens and some endotoxins-producing Gram-egative bacteria [11–13]. Firstly, Bacteroidetes/Firmicuteslteration may modify the host energy metabolism through apecific polysaccharide utilization loci mechanism [14]. More-ver, the accumulation of gut-derived bacterial inflammatoryolecules (e.g. LPS, peptidoglycans and flagellin) in intestine

s thought to accelerate the inflammation in T2DM [15,16].esides, gastric bypass surgery, an effective way to normalize

he blood glucose level to treat T2DM, could reduce body weightue to the alteration of the microbiome at the distal gut [17].

It has been confirmed that some probiotic strains are ableo modulate blood glucose homeostasis, and hence improve2DM [18]. Several mechanisms have been proposed. Firstly,robiotic could acted as an effective immune system modulatorgainst altered-microbiota induced chronic inflammation.t is well-established that obesity induced chronic low-levelnflammation is a leading cause of the progression of T2D19,20,21]. Some probiotics have been confirmed to preventnset of diabetes through down-regulating inflammatory IFN-�nd IL-2 or IL-1� or enhancing anti-inflammatory IL-10roduction in diabetic animal studies [22–24]. Recently, Lacto-acillus reuteri GMNL-263 have been demonstrated to suppresserum glucose, insulin, leptin, C-peptide, glycated hemoglobin,LP-1 level, inflammatory IL-6 and TNF-� in adipose tissues

nd PPAR-� and GLUT4 gene expression in high fructose-fedats [25]. Furthermore, human studies have revealed thatrobiotic yoghurt consumption could reduce hs-CRP level andmprove HOMA-IR score in pregnancy which is also considereds metabolic syndrome [26,27]. In addition, some probiotictrains show favorable antioxidative effect which is one of theffects against chronic inflammation. They are apparently ableo alleviate pancreatic oxidative stress which can lead to chronicnflammation and apoptosis of pancreatic �-cells [28,29].

Moreover, the supplementation of certain probiotic strainsan potentially modulate the lipid metabolism and result inhe reduction of the serum total cholesterol level and LDL-holesterol, which will reduce the risk of T2DM [30]. Besides,ndotoxemia has been identified as a triggering factor of insulinesistance in mice, making the suppression of endotoxemiay probiotic another potential protective mechanism [9]. Anral administration of Lactobacillus casei Shirota, was able tonhance the expression of plasma lipopolysaccharide-bindingrotein (LBP) and consequently reduce endotoxemia in murine

odels of obesity and T2DM [31]. In another study, the

onsumption of the probiotic strain, Bifidobacterium animalisubsp. lactis 420, suppressed the bacterial translocation pro-ess from intestine to tissues, which might lead to metabolic

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uman Wellness 2 (2013) 167–172

acteremia in the early onset of T2DM [32]. From the perspec-ive of nutrition, a novel probiotic strain, L. casei Zhang, wasecently proven to exhibit osteocalcin-elevating effect leading tomprovement of oral glucose tolerance in impaired glucose toler-nce (IGT) rats. This was probably achieved via gut Bacteroidesragilis enriched vitamin K2 mechanism [33].

. Microbiota and T2DM complications

.1. Diabetic retinopathy

Diabetic retinopathy accounts for more than 60% incidencen T2DM [34]. As expected, a higher frequency of Gram-positiveacteria and a higher proportion of coagulase negative staphylo-occi was detected in diabetic patients, especially those withetinopathy [35,36]. This result was supported by Bilen et al.,ho found that Staphylococcus epidermidis and Staphylococ-

us aureus were the predominant conjunctival organisms in2DM patients, and the frequency of S. aureus isolated from

he patients’ eyes were higher than that of T1DM and healthyubjects [37]. Parkinson’s disease is also one of complicationsith chronic diabetic neuropathy in T2DM [38]. Kusbeci et al.bserved that the occurence of S. aureus was significantly highern the conjunctival flora of Parkinson’s patients than in healthyontrols [39].

.2. Renal toxicity and kidney stones

A high proportion of T2DM patients also suffer from clinicalondition of chronic kidney toxicity, such as kidney stones. Thiss probably due to the disruption of colonic epithelial perme-bility which was implicated in the pathogenesis of T2DM andhronic kidney toxicity [40]. By phylogenetic microarray analy-is, chronic kidney disease patients showed significant changesn 190 microbial operational taxonomic units (OTUs), particu-arly the high abundance of the Enterobacteriaceae comparedo the healthy control group [40].

Moreover, Zheng et al. recently demonstrated that the biocon-ersion of melamine by gut microbiota, particularly Klebsiella,as essential for renal toxicity and the formation of crystal

tones [41]. Oxalobacter formigenes, a commensal gut microbe,as been shown to improve the clinical condition of kidney stoneatients [42]. However, commonly available probiotics, includ-ng Lactobacillus and Bifidobacterium species, were insufficientn degrading oxalate to treat kidney stones [43,44]. Besides, thextent of calcium oxalate stone formation may be dependent onhe microbiota. This is evidenced by the low expression levelf vitamin K epoxide reductase complex subunit 1 (VKORC1)n patients with calcium oxalate urolithiasis. The expression ofKORC1 could be influenced by vitamin K2 producing gutacteria [45,46].

.3. Hypertension

Hypertension and T2DM are closely related to each othern clinical setting. Apart from being a complication to T2DM,t is also a major risk factor for cardiovascular disease and a

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ymptom of metabolic syndrome. Recent evidence suggests thatetabolic syndrome is partially regulated by the gut micro-

iota [6]. However, only very little is known about the rolef the host gut microbiota in the case of hypertension. Onexperimental finding supporting the hypothesis of blood pres-ure regulation by the gut microbiota was provided by Pluznickt al. using a mouse model. Propionate is one of the end-roducts derived from the gut microbiota. It was revealedhat, in response to propionate, the expression of renal olfac-ory receptor 78 (Olfr78) was increased, in turn mediatinghe secretion of rennin [47]. Consequently, the blood pres-ure was elevated. On the contrary, G protein-coupled receptorGPR41), a short-chain fatty acid receptor, negatively regu-ated the blood pressure. Hence, it was concluded that these gut

icrobiota-derived short-chain fatty acids, in particular propi-nate, participated in the blood pressure regulation process viaoth receptors.

Furthermore, it has been reported that Lactobacillus john-onii La1 ingestion could not only maintained low bloodlucose level in streptozotocin (STZ)-induced diabetic rats,ut also prevent rats from elevated blood pressure by reduc-ng the renal sympathetic nerve activity and enhancing thearasympathetic nerve activity through the sympathoadrenalxis [48,49].

.4. Atherosclerosis

Most T2DM patients tend to have higher levels of serumipids, which predisposes them to atherosclerosis. Associationsetween microbiota and atherosclerosis have been proposed.oren et al. analyzed the oral, gut and atherosclerotic plaqueicrobiota in atherosclerotic patients [50]. Good correlation was

ound between total abundances of Veillonella and Streptococcusn the oral cavity and the atherosclerotic plaque. Moreover, sev-ral oral and intestinal bacterial taxa, including Streptococcus,eisseria and Fusobacterium, are correlated with the plasmaholesterol levels.

It is well established that probiotics with bile salt hydrolasectivity could accelerate the bioconversion of cholesterol to pri-ary bile, showing acids a serum lipids-reducing effect [30].oroti et al. reported that the administration of a synbiotic bev-

rage called shake, which contained Lactobacillus acidophilus,ifidobacterium bifidum and oligofructose, markedly increased

he plasma HDL cholesterol and decreased the condition ofasting glycemia in elderly T2DM patients [51].

.5. Cystic fibrosis

Patients with cystic fibrosis (CF) are also associated withigh incidence of T2DM [52]. There is increasing evidence thatn altered microbiota in CF respiratory tract plays an importantole in its pathogenesis. The most commonly isolated bacterialpecies in airways of CF patients were Haemophilus influenzae,

. aureus, Pseudomonas aeruginosa and Burkholderia cepaciaomplex species [53]. Nowadays, high-throughput sequencingethods, such as 16S amplicon pyrosequencing, were applied

o evaluate the whole composition of the airway microbiota.

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uman Wellness 2 (2013) 167–172 169

oddard et al. found that CF lungs were typically dominated bynly one to three species by direct sampling of explanted lungs54]. They also observed that the microflora in the sputum andhroat specimens could not represent the typical CF microflora.

A recent study monitoring the development of gut andespiratory microbiomes in CF infancy revealed that both com-artments shared some common core microbes and the temporaluctuation of microbiota over time was in concordance withach other. Moreover, a change in diet resulted in the alter-tion in the airway microbiota composition [55]. These togetheruggest that diet, gut microflora and the development of theespiratory tract microbiota are linked with one another. Becausef this link, it is logical to hypothesize that the oral adminis-ration of probiotics may reduce symptoms caused by CF. Ateast two individual studies confirmed the probiotic effects ofactobacillus GG in alleviating the intestinal inflammation andulmonary exacerbations rate in CF patients [56,57]. Anotherommon symptom of CF children is the malabsorption of bilecids. Roy et al. showed that antibiotic treatment reversed thisondition, which was due to the reduction of gut anaerobesnd their related enzymatic activities, such as bile salt hydro-ase (BSH) [58]. Gut bile salt hydrolases deconjugate glycine oraurine from bile salts. The deconjugated bile salts are more effi-ient in lipid emulsification and absorption in the gut. Hence, thepplication of BSH-bearing probiotics may be another potentialreatment for CF patients.

.6. Diabetic foot ulcers

Diabetic foot ulcers leading to infection and limb loss are bothinked to an increasing risk of age-related diabetes. Several well-xplored microorganisms, including Staphylococcus species, P.eruginosa and E. coli, etc., were isolated from patients withnfected diabetic foot ulcers [59]. The main plantar foot normalora are coagulase-negative Staphylococcus species, which areecognized as strong competitors for the infection-associated. aureus. Recently, Redel et al. found that the ratio of non-athogenic Staphylococcus to pathogenic S. aureus on the feet ofiabetic men was lower, compared to the normal subjects [60].y bacterial 16S rRNA gene pyrosequencing, Gardner et al.nalyzed the microbiomes in diabetic foot ulcers and revealedhat the ulcer depth and duration were negatively correlated withhe abundance of Staphylococcus, whereas the ulcer durationas positively correlated with that of Proteobacteria [61].

.7. Alzheimer’s disease

T2DM may result in an increase in risk in Alzheimer’sisease (AD) and these may share common pathogenic mecha-isms [62,63]. Vignini et al. summarized the recent experimentalvidence and potential mechanisms that link the two medicalonditions, including the possible roles of insulin deficiency

r insulin resistance in facilitating cerebral �-amyloidogenesis,hich accounts for the increased risk of diabetes patients toementia [64]. In addition, AD had even been considered as theype 3 diabetes [65].

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Currently, little data is available on the resident microfloraf AD patients, thus how they are related to each other remainsoorly understood. To date, only one study has directly com-ared the gut physiology and microbiota structure between wildype and AD transgenic mice. The gut alteration in AD trans-enic mice was characterized by an increase of Gram-negativeacteria accompanied by mucosal disruption [66]. Moreover, themyloid precursor protein (APP) expression level was signifi-antly upregulated in the intestine of AD, but not in the controlice.Even though the research area of the gut microbiota in AD is

nderstudied, the possibility of preventing from or treating ADia enteria bacteria has been considered. Indole propionic acidsIPAs) are putative drugs for treating AD and T2DM [67,68].he plasma amino acid metabolites, including the bioactive

ndole-containing metabolites, of germ-free mice were signif-cantly affected as compared to the normal mice. Moreover, theioconversion of indole to indole-3-propionic acid was foundo be solely dependent on the gut microbiota [69]. Therefore,

anipulations of gut microbiota seem to be a key to restore thelasma IPA level. Another metabolic characteristic of AD washe loss of GABA(A) receptors in the hippocampus of the brain70]. The probiotic strain L. rhamnosus JB-1, an effective mod-lator of the gut microbiota, was proved to be able to increaseABA(A�2) in the hippocampus of mice [71]. These are direct

vidence showing the interaction between the residence flora andhe host metabolism, which offers novel potential prophylaxisr treatment targets for AD.

. Anti-T2D regimens concerning microbiota

In recent years, due to side-effects of anti-T2D drugs forlucose or insulin resistance control (e.g. metformin and piogli-azone) and anti-inflammatory drugs for T2D complications (e.g.SAIDs), natural anti-T2D compounds extracted from plantsotentially with less side effects have drawn more attention4,72]. Particularly, these drugs with GI and cardiovascular sideffects brought high risks for long-term use [73]. Berberine,

component from traditional Chinese herb Coptis chinensis,as been recently demonstrated to have anti-diabetic effecthrough modulating microbiota composition since it is mainlybsorbed by gut [74]. The major bioactive constituents of Gins-ng, another important anti-diabetic Chinese herb, were mainlyrom microbiota-mediated metabolism of ginsenosides [75].nhibition of intestinal α-glucosidase is another strategy to con-rol the increase in blood glucose at early onset of T2D [76].owever, drugs for this target may lead to GI side effects [77].

great deal of polyphenols, a series of natural compounds fromea, coffee, wine, fruit, vegetables, and chocolate, can inhibitlucose metabolism enzymes to exert anti-diabetic effect witho side effect [78,79]. Typically, wine polyphenols have been

onfirmed to significantly modulate some taxa of gut microbiotand reduce serum lipids and inflammatory C-reactive protein inumans [80]. Moreover, the microbiota is also important for theetabolism of polyphenols (e.g. catechin and gallocatechin from

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uman Wellness 2 (2013) 167–172

reen tea) promoting their bioavailability in the small intestine81].

. Conclusion

In summary, great progress has been made in the field of theesident microbiota in T2DM in recent years. Microbiota con-ributes not only to low-level inflammation in the onset of T2D,ut also to the further development of T2D through inflammatoryomponents. It has also been extended to various T2DM relatedomplications, including diabetic retinopathy, kidney toxicity,therosclerosis, hypertension, diabetic foot ulcers, cycstic fibro-is and Alzheimer’s disease. These studies together support therucial role of microbiota in maintaining the intestinal barrierntegrity, sustaining a normal metabolic homeostasis, protectinghe host from infection by pathogens, enhancing host defenseystem and even influencing the nervous system in T2DM.

icrobiota-mediated mechanism is also involved in some anti-2D regimens using natural compounds from plants. However,

he potential mechanisms linking the microbiota to T2DM haveot been fully elucidated and continuing research efforts areeeded.

cknowledgements

This research was supported by the National Natural Sci-nce Foundation of China (No. 31025019), the Innovation Teamevelopment of the Ministry of Education of China (Grant No.

RT0967).

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